Sustained relief analgesic compositions



Aug. 18, 1970 w. M. HOLLIDAY ETAL 3,524,910

SUSTAINED RELIEF ANALGESIC COMPOSITIONS Filed June 9, 1969 2SI100I$-SI100L l ANALGESIC RELIEF (ARTHRITIS) DESIGN: THREE-WAY,DOUBLE-BLIND,CROSS-OVER, RANDOM ORDER DOSAGE AND APPROXIMATE TIME coneTOTALIgr/Doy) 7 a.m. "0. m. 3 P.m. 7 p.m. I p.m.

SRA-ZO P SIRA-ZO P $RA-2O 6O A-ZO P A-ZO P A-ZO 6O A-IZ A-I2 A- I2 A-IZA-IZ 6O PATIENTS: 26- SRAZ SUSTAINED-RELEASE ASPIRIN WEEKS ON EACH DRUG!2 AZ REGULAR ASPIRIN RESULTS 1 (AVERAGE OF 26 PATIENTS) P: PLACEBO 5 x wI Q E I z a 0 n.

0 ON MORNING AFTERNOON EVENING ARISING STATISTICAL ANALYSIS OF RESULTSON ARISING MORNING AFTERNOON EVENING SRA-ZO VS A-ZO O.I% IO% IO'A 5% 0,.HQ SRA-ZO VS A-IZ O.I% IOII- 5% N38 N53 A-ZO VS A-IZ N35 N35 5% 2% I.O%

F I G. I INVENTORS WILLIAM M. HOLLIDAY MURRAY BERDICK SAUL A. BE LL BYGEORGE C. KIRITSIS TOTAUqr/Doy) 2 Shoots-Shoot .2

I I pm.

SRA- 20 SRA- 20 A-ZO DOSAGE AN) APPROXNATE TIME ll am.

W. M. HOLLIDAY F-TAL sRA-2o A-zo Aug. 18, 1970 SUSTAINED RELIEFANALGESIC COMPOSITIONS Filed June 9, 1969 CODE 'Illllllll INVENTORSWILLIAM H. HOLLIDAY MURRAY BERDICK SAUL A. BELL ATTORNEYS NIGHTTIMEAWAKEMNG NSS GEORGE C. KIRITSIS STIFFNESS STATISTICAL ANALYSIS OFRESULTS MORNING STIFFNESS DISCOMFORT Nss 5 O 5 O 2 2 l l o 2 T E A m A Tm I m w P I s .r N Z A q a A A m E R E L I E P M R S W. A IT D H A E R oG N A B T .l M L E N T U C 5 G A 2 U E L S R P A L\\\\\\ \\\\N\\\\ m A Al R I s R O Q T 1 M A 5 o 5 o 5 0 Z 2 I I O XuQZ kmomzooma m0 mmmzmuzhwsun-2b vs A-ZO SRA-ZO vs A-lz A-2O vs A-IZ United States Patent3,524,910 SUSTAINED RELIEF ANALGESIC COMPOSITIONS William M. Holliday,Madison, Murray Berdick, Branford, and Saul A. Bell, New Haven, Conn.,and George C. Kiritsis, Richmond, Va., assignors to Sterling Drug Inc.,New York, N.Y., a corporation of Delaware Continuation-impart ofapplication Ser. No. 508,528, Nov. 18, 1965. This application June 9,1969, Ser. No. 831,624 The portion of the term of the patent subsequentto Jan 6, 1987, has been disclaimed Int. Cl. A61 3/07, 3/10; A61k 9/04US. Cl. 424-35 3 Claims ABSTRACT OF THE DISCLOSURE An oralsustained-release analgesic composition consists essentially of aspirinof specified size and shape encapsulated with a continuous thin coatingof ethyl cellulose, the weight ratio of aspirin to ethyl cellulose beingin the range from 22:1 to 50:1.

This invention relates to novel pharmaceutical compositions andtechniques for providing sustained analgesic relief employingacetylsalicylic acid (aspirin) as the active therapeutic agent. Thenovel compositions of the present invention is an analgesic preparationcomprising ethyl cellulose encapsulated particles of acetylsalicylicacid wherein the relative thickness of the ethyl cellulose layer to theacetylsalicylic acid layer is such that substantially all of theencapsulated acetylsalicylic acid will be gradually released into theblood by a diffusion mechanism over a period of four hours upon oraladministration which surprisingly affords eight hours of analgesicrelief.

This application is a continuation-in-part of our copending applicationSer. No. 508,528, filed Nov. 18, 1965 now U.S. Pat. No. 3,488,418.

Prior to the present invention there have been prepared various types oftimed release pharmaceutical preparations containing aspirin as theactive ingredient. Most, if not all, of the heretofore used timedrelease aspirin preparations have not been truly effective for providingsustained analgesic relief over a relatively long period of time.

The failure of many of the heretofore known timed release aspirinpreparations can be attributed to a failure of prior investigations toappreciate fully the chemical and physiological factors involved whenaspirin is taken into the body as a therapeutic agent, particularly Withrespect to its analgesic and anti-inflammatory activities.

It is a recognized fact that with aspirin the maximum time ofeffectiveness as an analgesic is only a few hours due to the biochemicaldecomposition of aspirin in the body. Accordingly, when used as ananalgesic the patient must take repeated dosages every few hours. Also,the extent of relief will fluctuate between dosages since the analgesiclevel will constantly decrease due to the aforementioned biochemicaldecomposition of the analgesic in the body.

Heretofore, many attempts have been made to overcome the aforementioneddrawbacks of conventional aspirin tablets by providing aspirin in theform of timed release pharmaceutical preparations whereby aspirin isreleased into the blood stream over a relatively long period of time,generally over an 8 hour period. Most of these prior preparations failedto give truly effective analgesic relief over the desired period for thereason there was not maintained in the body over the desired 3,524,910Patented Aug. 18, 1970 period an effective degree of analgesia. Inshort, when such preparations are employed, the active analgesiccomponent (aspirin) decomposes to an inactive state at a faster ratethan it is introduced into the blood system so that the overall level ofactive component is to low to exert effective analgesic relief over thedesired period.

Other preparations have used a combination of free aspirin and sustainedrelease aspirin to provide both immediate and prolonged results. In suchsystems, solid aspirin particles are in contact with the sensitivegastric mucosa. Many investigators consider such contact to be a causeof gastric irritation and gastric bleeding.

Objects and advantages of the invention will be set forth in parthereinafter and in part will be obvious herefrom, or may be learned bypractice with the invention, the same being realized and attained bymeans of the steps, methods and compositions described herein.

Among the objects of this invention is to provide aspirin preparationsand techniques which:

(a) Release a portion of aspirin rapidly when ingested for promptanalgesic effect and which sustain release of the remaining aspirin overan extended period of time to provide an analgesic effect of prolongedduration.

(b) Permit safely taking a single convenient sized dose of aspirin atless frequent intervals to provide analgesic relief equivalent to takingUSP aspirin tablets at one half the dosage twice as frequently.

(c) Maintain effective analgesic and anti-inflammatory relief from abedtime dose throughout the night, continuing until arising.

(d) Permit safely taking double the conventional dose of aspirin used inproducts for self-medication without the usual aspirin side effects toobtain prolonged analgesic effectiveness. Such a double dose (20 grains)of aspirin taken as ordinary aspirin tablets produces uncomfortable sideeffects of dizziness and tinnitus in most individuals and does notappreciably prolong the duration of analgesic effectiveness obtainedwith a single dose of aspirin (10 grains).

(e) Provide constant analgesic effectiveness over a prolonged period oftime which does not decrease between doses to the degree observed withmore frequent doses of ordinary aspirin.

(f) Prevent contact of solid aspirin particles with the sensitivegastric mucosa.

It has been found that the objects of this invention may be realized byproviding an analgesic preparation comprising: ethyl celluloseencapsulated particles of acetylsalicylic acid wherein (a) the amount ofethyl cellulose to acetylsalicylic acid can vary from l-22 to l parts byweight, (b) the acetylsalicylic acid particles are distributivelyarranged so that substantially all are caught on a screen having 0.149mm. openings, a major portion are caught on a screen having 0.250 mm.openings and substantially all will pass a screen of 0.841 mm. openings,the preponderance of acetylsalicylic acid particles in greatestdimension being not more than twice their second dimension and not morethan four times their smallest dimension. The thinness of the ethylcellulose coating is such that the size of the ethyl celluloseencapsulated aspirin particles is essentially the same as the size ofthe uncoated aspirin particles.

Preparations of the above type are characterized by the fact thatsubstantially all of the encapsulated acetylsalicylic acid will begradually released into the blood by a diffusion mechanism, over aperiod of four hours upon oral administration which surprisingly affords8 hours of analgesic relief. Based upon the unusual favorable clinicalresults obtained by the use of the analgesic preparations of thisinvention, it appears that the acetylsalicylic acid is released into theblood at such a rate that optimum blood levels of acetylsalicylic acidare maintained for about four hours.

The ethyl cellulose encapsulated particles or granules of aspirin of theinstant invention can be utilized in dosage composition per se, eitheralone or in gelatin capsules, or in the preferred compressed tabletform, the latter preferred tablet form being disclosed and claimed inour said copending application Ser. No. 508,528, now US. Pat. No.3,488,418.

In order to appreciate fully the attributes of this invention, it isthought advisable to discuss to some extent the mechanisms involved whenthe above mentioned encapsulated aspirin preparations are taken into thebody.

When ingested, the individual granules of encapsulated aspirin aredispersed in the stomach. The gastric fluids slowly diffuse in throughthe thin micro-capsule walls, dissolve the aspirin, and slowly diffuseout again. The rate of this process is determined by the nature of thewall material, by the thickness of the wall (so long as it is acontinuous film) and by the nature of the environment. The environmentis a changing one, since it is influenced by the amount of nature offluids and foods ingested. After some time which varies from individualto individual and from one occasion to another occasion, the contents ofthe stomach pass into the duodenum, then to the small intestine, then tothe large intestine, then to the bowels. This provides a changingenvironment thereby influencing the rate at which active drug isextracted from the microcapsules of aspirin and made available forabsorption through the walls of the stomach and intestines into thebloodstream.

The picture is further complicated by the fact that under conditionsfound in the stomach, in the intestines, and in the bloodstream,acetylsalicylic acid (ASA) is hydrolyzed to yield salicylic acid (SA).Both ASA and SA are recognized as effective analgesics; most medicalexperts agree that ASA is a more potent analgesic.

Sustained release medications can be characterized by widely used invitro techniques of measuring the rate of extraction of active drugunder standard laboratory conditions. Using such techniques as a guide,relatively thickwalled micro-capsules were first tried in vitro,releasing approximately half of their acetylsalicylic acid content inthe first hour, and then slowly and constantly releasing the remainderof the drug over the next 6 to 8 hours. Using this preparation in vivo,very little acetylsalicylic acid can be found in the blood beyond 2hours. Reducing the wall thickness produced a higher ASA level for 2hours, and produced a higher salicylate level over 8 hours, but did notimprove the ASA blood level appreciably beyond the 2 hour period. Itappeared that some unknown factor was interfering with the transfer toASA, but not SA, from the micro-capsules into the bloodstream. It wasnot until a drastic reduction of wall thickness was tried in the face ofcontrary prior evidence, that a rate of transfer of ASA from the ethylcellulose encapsulated aspirin granules or tablets prepared therefrom tothe bloodstream was achieved that provided optimum blood levels ofacetylsalicylic acid for a prolonged period of time. By achievingoptimum blood levels for about four hours, it was discovered thateffective sustained analgesic relief and anti-inflammatory relief couldbe achieved for an 8 to 12 hour period. While the exact biological orphysiological mechanisms involved when aspirin exerts its analgesic andanti-inflammatory actions are not known, apparently such activities arenot only exerted when aspirin is in the bloodstream but also when it isremoved from the bloodstream and carried to other portions of the body.

A clinical study of analgesic relief proved the advantages of thepharmaceutical preparations of this invention over two different dosageregimens of regular aspirin, at the same total daily dose. Thisout-patient study was a three-way, double-blind cross-over on 26 caseswith rheumatoid arthritis and fibrositis, in which 20 grains of thetablet composition of Example I (described hereinafter in detail andreferred to herein as Sustained Release Aspirin (SRA 20)) evey 8 hours(with intervening placebos) was compared with 20 grains of regularaspirin (A-20) every 8 hours (with intervening placebos), and 12 grainsof regular aspirin (A-12) every 4 hours for five doses.

The study was conducted in a major rheumatology clinic by a highlyqualified clinical investigator.

The principal results are shown in Tables I and II, and FIGS. 1 and 2 ofthe accompanying drawings. It will be noted that in the graphs of FIGS.1 and 2, at the bottom of each graph is a statistical analysis of theresults, for each interval of time (in FIG. 1) and for eachcharacteristic observed (in FIG. 2). Each entry in the tabulatedanalysis is a statement of the statistical significance of differencesbetween pairs of results. Where a percentage is stated, this is thelikelihood that the result could have occurred by chance. Thus, 0.1%means that there is statistical assurance of greater than 99.9% that thedifference observed is real and meaningful. In clinical studies withdrugs, a statistical assurance of 95% or more is usually accepted byexperts as significant. (Thus, in the tabulations of FIGS. 1 and 2, allfigures of 5% or less mean the differences are significant.) NSS meansNo Statistical Significance. Thus, all pairs of results marked NSS canbe considered as identical from a statistical point of view.

TABLE I.-OVERALL DRUG PREFERENCE SRA-20 A-20 11-12 (20 gr. q. 8 h.) (20gr. q. 8 h.) (12 gr. (1. 4 b.)

No. Percent No. Percent No. Percent Patient Choice:

First 19 73. 1 0 0 1 3. 8 Second- 1 3. 8 6 23. 1 6 23. 1 Third 0 0 7 26.9 6 23. 1 Second/Th 0 0 7 26. 9 7 26. 9 No difference- 6 23. 1 6 23. 1 623. 1 Physician Evaluation:

First 23 88.5 0 0 2 7. 7 0 0 6 23. 1 12 46. 2 O 0 12 46. 2 6 23. 1 2 7.7 7 26. 9 5 19. 2 No difference 1 3. 8 1 3. 8 1 3. 8

TABLE II.SYMPTOM INDICES BY TIME OF DAY SBA-20 11-20 11-12 (20 gr. q. 8h.) (20 gr. q. 8 h.) (12 gr. q. 4 h.)

Previous Night:

Discomfort 1. 21 1. 89 1. No. of times awake .1. 20 2. 29 2. 45

* Based on scale:

Severe, 3.

Moderate, 2.

Slight, 1.

None, 0.

The study clearly indicates the superiority of an aspirin preparation ofthis invention (SRA-20) to either dosage schedule of regular aspirin(A-20 and A-12). Despite the complete blinding of the medications by themethod of coding employed, 19 of the 26 patients preferred SRA20 toeither of the other medications, A-20 and A-12, and only one preferredthe regulator aspirin q4 h A12, with the other six finding nodifference. Objectively, the physician considered SRA-ZO superior to theA-20 and A-l2 in 23 of the 26 patients, largely because of its greatereffectiveness during the night and on arising. This was manifested by asuperior score for SRA-20 over A-20 and A12 (which wereindistinguishable from each other) in nighttime discomfort, number oftimes awake at night, pain on arising, and morning stiffness. Themorning pain score for SRA-20 continued to be better than that for A-20and A-12, although the difference no longer reached statisticalsignificance. During the afternoon and evening,

SRA-20 was indistinguishable from the 12 grains of aspirin, A-l2, takenevery four hours, but both of these were superior to the 20 grains ofaspirin every 8 hours, A-20, with the difference reaching highstatistical significance in the evening. No appreciable number of sideeffects of any sort were reported, but this was not surprising, becausethese were patients who had been on regular aspirin for their arthritisfor some time.

In passing, it may be mentioned that in arriving at the instantinvention, the criterion used in evaluating effective analgesia is theacetylsalicylic acid level in the blood. This approach is quitedifferent from the criteria normally used in predicting analgesia foraspirin. More particularly, heretofore, it has been the usual practiceof investigators in the aspirin timed release field who were trying toachieve effective analgesia over a long period of time to assume thatanalgesia was related to the salicylate level in the blood, the latterlevel encompassing salicylic acid and acetylsalicyclic acid (aspirin).

It is our view that the above referred to criteria heretoforeconventionally used for evaluating analgesic level based on salicylicacid level or salicylate level are not an accurate guide for determininganalgesic level. Instead a much more realistic guide for evaluatinganalgesia is the acetylsalicyclic acid level in the blood.

As indicated hereinbefore, under the conditions found in the stomach, inthe intestines, and in the bloodstream, acetylsalicylic acid (ASA) ishydrolyzed Within a short period of time toyield salicylic acid (SA).The aforementioned attributes of ASA over SA as an analgesic serve tosupport our view that determination of ASA level is a more significantguide for evaluating analgesic activity of an aspirin dosage form thaneither the salicylic acid blood level or total salicylate blood level.

Preferably, the encapsulated aspirin formulations used in accordancewith the instant invention are employed in the form of tablets. Typicaltablets of sustained release aspirin are made from:

Percent by weight Encapsulated aspirin 95 Tabletting excipients 5Microcrystalline cellulose (Avicel, made by American Viscose Corp.).

Guar gum Tale, U.S.P.

Cornstarch, U.S.P.

employed in such combination, and tabletted under such conditions thatthe thin walls of the encapsulated aspirin granules are not cracked orsmashed. The composition must provide a tablet that will withstandstorage and shipping without chipping or breaking, but will disintegratequickly and easily when wetted by saliva or gastric fluid, to givediscrete particles of encapsulated aspirin.

Tablets of sustained release aspirin can be made to contain anyconvenient dose of aspirin. Typical adult tablets contain 5, 7.5 or 10grains of aspirin, the latter being about the largest that can be easilyswallowed by most people. Childrens tablets can typically contain 2.5grains of aspirin.

Tablets of sustained release aspirin can contain up to 96% of activeingredients, aspirin (acetylsalicylic acid). There is no critical lowerlimit. However, from the practical point, tablets containing less thanabout 75% aspirin are too bulky for easy swallowing of a typical dose ofaspirin or require an excessive number of tablets per typical dose.

The granules of encapsulated aspirin could alternatively be put inconventional pharmaceutical gelatin capsules (without tablettingexcipients) to give sustained release aspirin capsules. The twopractical disadvantages of this form of the product are that thecapsules would be much bulkier than tablets (which are highlycompressed) and that the active medication would be considerably delayed(by at least half an hour) in being released. Alternatively, saidgranules of encapsulated aspirin can be used alone in other dosageforms, e.g., in individual unit dosage packets of the granules.

As indicated hereinbefore, the encapsulated aspirin used in accordancewith this invention consists of individual granules, or aggregates ofparticles of aspirin which have been coated with a thin wall of ethylcellulose built to the desired thickness by programmed control ofcooling rate and agitation rate and employing in the pro duction of theencapsulated aspirin a weight ratio of aspirin core material to ethylcellulose shell material in the range of 22:1 to 50:1. Also, asindicated heretofore, the aspirin particles are distributively arrangedso that substantially all are caught on a screen having 0.149 mm.openings, the word substantially is used to include the existence offines that may be present. A major portion are caught on a screen having0.250 mm. openings, and substantially all will pass a screen of 0.841mm. openings. The word substantially is used in the aforementionedstatement to include the existence of agglomerates that may be present.

In forming tablets, conventional pharmaceutical tabletting equipment maybe employed, if precautions are taken to avoid breaking open theencapsulated particles. One of the most important precautions is toselect the optimum particle shape of encapsulated aspirin. Since theencapsulation process does not alter particle shape, this means thatselection of the particle shape of the starting aspirin is necessary.Many commercially available forms of aspirin are crystalline rods havinga ratio of length to thickness as high as 5:1. Such elongated rods areeasily broken when subjected to tabletting pressures. Particles thatwill effectively resist breaking when subjected to tabletting pressuresare those wherein their great est dimension is not more than twice theirsecond dimension, and not more than four times their smallest dimension.We find it preferable to utilize particles of aspirin that have beenformed from compacted crystals of aspirin, since such particles haveless tendency to change their release rate after being subjected to thepressure of the tabletting operation.

The following are specific examples of aspirin sustained reliefpreparations formed in accordance with this inven tion. Examples A, B, Cand D relate to the preparation of encapsulated aspirin of calculatedaspirin content ranging from 95.5-97.5% while Examples 1 and 2 relate tothe manufacture of tablets from the encapsulated aspirin preparations ofExamples C and D respectively.

EXAMPLE A This example utilizes the procedures and techniques disclosedin US. Pat. 3,155,590 wherein cyclohexane is the solvent vehicle,aspirin is the core material, ethyl cellulose is the wall material, andbutyl rubber is em ployed to maintain the wall material solution as aseparate phase. The aspirin particles are distributively arranged sothat substantially all are caught on a screen having 0.149 mm. openings,a major portion are caught on a screen having 0.25 0 mm. openings andsubstantially all will pass a screen of 0.841 mm. openings. The granularaspirin particles are in the form of chunky particles wherein thepreponderance of the particles in greatest dimension are not more thantwice their second dimension, and not more than four times theirsmallest dimension. The ethyl cellulose has an ethoxyl content ofsubstantially 49.1% by weight, and a viscosity of 103 to 108 centipoisesas a 5% by Weight solution in a 20% alcohol/toluene solvent. The butylrubber has a viscosity of 60-75 Mooney 8-minute reading at 212 F. Theintended ratio of core material to capsule Wall is 22:1.

Into a suitable vessel, there are introduced with agitation:

505 pounds of a 3% by weight solution of the solution of the specifiedbutyl rubber in cyclohexane,

7 1135 milliliters of acetic anhydride, 4 pounds of the specified ethylcellulose, and 88 pounds of the acetylsalicyclic acid,

to form a system which is heated to 80 C. and agitated sufiiciently toproduce minute liquid entities of ethyl cellulose-cyclohexane solutiondispersed among particles of aspirin. The system is cooled withcontinued agitation and the liquid entities of Wall-forming materialdeposit on the aspirin particles. The cooling is carried on to roomtemperature, the capsules then being recovered by decantation,filtering, centrifuging or the like. For purification, the capsules arewashed with cyclohexane and refiltered to remove any entrained butylrubber, and thereafter they are dried.

The capsules produced in this example are substantially 95.4% aspirinand release substantially 40% of their aspirin content when agitated insimulated gastric fluid at 37 degrees centigrade for 1 hour, and may beused for preparing dosage forms.

EXAMPLE B This example makes use of a system similar to that disclosedin Example A except that low molecular weight polyethylene resin havinga viscosity in the range of 7,500 to 10,000 centipoises at 150 degreescentigrade, such as Epolene C-lO now supplied by Tennessee Eastman Chemical Company, is used to maintain the wall material solution as aseparate phase. The intended ratio of core material to capsule wallmaterial is 28: 1.

Into a suitable vessel, there are introduced with agitation:

500 pounds of a 2% by weight solution of the specified low molecularweight polyethylene resin in cyclohexane,

1135 milliliters of acetic anhydride,

4 pounds of the specified ethyl cellulose, and

112 pounds of the specified particulate size acetylsalicyclic acid,

to form a system which is heated to 80 centigrade and agitatedsufficiently to produce minute liquid entities of ethylcellulose-cyclohexane solution dispersed among particles of aspirin.Cooling and agitation are carried on, the individually coated aspirinparticles are recovered and washed for purification and thereafter driedas disclosed in Example A.

The capsules produced in this example are substantially 96.0% aspirin,and release substantially 53% of their aspirin content when agitated insimulated gastric fluid at 37 C. for 1 hour, and may be used forpreparing dosage forms.

EXAMPLE C This example makes use of a system similar to that disclosedin Example B except that the intended ratio of core material to capsulewall material is 35:1.

Into a suitable vessel, there are introduced with agitation:

500 pounds of a 2% by weight solution of the specified low molecularweight polyethylene resin in cyclohexane,

1135 milliliters of acetic anhydride,

3 pounds of the specified ethyl cellulose, and

105 pounds of the specified particulate size acetylsalicyclic acid,

to form a system which is heated to 80 C. and agitated sufficiently toproduce minute liquid entities of ethyl cellulose-cyclohexane solutiondispersed among particles of aspirin. Cooling and agitation are carriedon, the individually coated aspirin particles are recovered and Washedfor purification, and thereafter they are dried as disclosed in ExampleA.

The capsules produced in this example are substantially 96.4% aspirin,and release substantially 61% of their aspirin content when agitated insimulated gastric fluid at 37 C. for 1 hour, and may be used forpreparing dosage forms.

EXAMPLE D This example makes use of a system similar to that disclosedin Example B except that the intended ratio of core material to capsulewall material is 50:1.

Into a suitable vessel, there are introduced with agitation:

1000 pounds of a 2% by weight solution of the specified low molecularweight polyethylene resin in cyclohexane,

2270 milliliters of acetic anhydride,

4.2 pounds of the specified ethyl cellulose, and

210 pounds of the specified particulate size acetylsalicyclic acid,

The following composition was mixed, using conventional pharmaceuticalprocessing equipment:

Weight Per Batch, tablet kg mg Percent;

Encapsulated aspirin of Ex. 0 (96. 4%

acetylsalicylic acid) 25.896 664 93.13 Avicel (microcrystallinecellulose)- 1. 365 35 4. 91 Cornstarch 390 10 l. 40 Guar gum 4 .56

This mixture was tabletted on a conventional pharmaceutical rotarytabletting machine, using capsule-shaped punches (length 0.627", width0.286") yielding tablets having a thickness of substantially 0.259, aweight of substantially 713 mg., a hardness of substantially 12.5 kg. bya Stokes tablet hardness tester, and a disintegration time of less than45 seconds in distilled water at 37 C. The tablets assayed 10.0 grainsASA/tablet, contained 0.05% SA, and released substantially 68% of theiraspirin when agitated in simulated gastric fluid at 37 C. for 1 hour.

The above described composition (SRA-20) is the analgesic preparationused in the clinical investigation referred to hereinbefore indiscussing Tables I and II and FIGS. 1 and 2 of the drawings.

EXAMPLE II The following composition was mixed, using conventionalpharmaceutical tabletting equipment:

This mixture was tabletted on a conventional pharmaceutical rotarytabletting machine using capsule-shaped punches (length 0.627", width0.286") yielding tablets having a hardness of substantially 10.5 kg. bya Stokes tablet hardness tester and a disintegration time of less than45 seconds in distilled water at 37 C. The tablets assayed 10.0 grainsASA/tablet, contained 0.06% SA, and released substantially 71% of theiraspirin when agitated in simulated gastric fluid at 37 C., for 1 hour.

As noted hereinabove, our invention comprehends unit dosage forms of ourethyl cellulose encapsulated aspirin granules, illustrated above asExamples A, B, C and D, other than the compressed tablet compositions ofExamples I and II. For example, unit dosages of said encapsulated,aspirin granules of Examples A, B, C and D containing 5.0, 7.5 or 10.0grains of aspirin per unit dosage are readily formulated in aconventional pharmaceutical gelatin capsule or in a conventionalpharmaceutical packet. In said unit dosage forms, the loose saidencapsulated aspirin granules are sealed in gelatin capsules or inpackets or envelopes made of a suitable pharmaceutically acceptablematerial, e.g., polyethylene laminated aluminum foil.

11: so desired, the therapeutic compositions of this invention includecombining the encapsulated aspirin preparations of the invention withother active components. For example, encapsulated aspirin could becombined with regular aspirin if it were desired to provide a greaterinitially available dose but still release the major portion of theaspirin slowly. If a material portion of the aspirin were to be added ina non-sustained form, then the release rate of the encapsulated portionof the tablet would have to be readjusted in order to provide theoptimum desired release for the tablet.

Typical of other drugs that might be combined with encapsulated aspirinto provide combination drugs are:

Phenacetin Sodium salicylate Caffeine Salicylamide AcetaminophenScopolamine Phenylephrine hydrochloride Glyceryl guaiacolateChlorpheniramine maleate Belladona alkaloids Dextromethorphanhydrobromide Ephedrine hydrochloride Phenylpropanolamine hydrochloride.

The invention in its broader aspects is not limited to the specificcompositions described but departures may be made therefrom within thescope of the accompanying claims without departing from the principlesof the invention and without sacrificing its chief advantages.

What is claimed is:

1. An orally ingestible analgesic dosage composition comprising: ethylcellulose encapsulated particles of acetylsalicylic acid wherein (a) theamount of ethyl cellulose to acetylsalicylic acid can vary from 1-22 to1-50 parts by weight, (b) the acetylsalicylic acid particles aredistributively arranged so that substantially all are caught on a screenhaving 0.149 mm. openings, a major portion are caught on a screen having0.250 mm. openings and substantially all will pass a screen of 0.841 mm.openings, the preponderance of acetylsalicylic acid particles ingreatest dimension being not more than twice their second dimension, andnot more than four times their smallest dimension, such aspirinparticles consisting essentially of compacted granules of crystallineaspirin.

2. The sustained analgesic relief preparation according to claim 1wherein the weight ratio of ethyl cellulose to acetylsalicylic acid is1:35.

3. The sustained analgesic relief preparation according to claim 1wherein the acetylsalicylic acid is in an amount from 2.5 to 10 grains.

References Cited UNITED STATES PATENTS 3,115,441 12/1963 Hermelin424-230 XR 3,146,168 8/1964 Battista 424-361 XR 3,155,590 11/1964 Milleret a1. 424-35 XR 3,341,416 9/1967 Anderson et a1. 424-35 XR 3,488,4181/1970 Holliday et a]. 424--35 OTHER REFERENCES Ecanow, Powders, pp.23-25 in Martin et al., Husas Pharmaceutical Dispensing, 5th ed. (1959).

United States Pharmacopoeia, Sixteenth Devision (USP XVI) pp. 931-932,934-935 (1960) U.S.P.C. Inc. Washington, D.C.

Lees, Fine Particles in Pharmaceutical Practice," J. Pharm. Pharmacol.15 (T), Suppl. pp. 43-55 December 1963.

SHEP K. ROSE, Primary Examiner US. Cl. X.R. 424-19, 230

3 3 3 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.152 5910 Dated August 18, 97

Inventofls) William M. Holliday et a1.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

. Column 2, line 5, 'to" first occurrence) should read --too--. Column3, line 22, of" (first occurrence) should read --and--. Column 4, line3, "evey" should read --every--; line 64, "regulator" should read --reular--. Column 5, lines 19 8a 25; column 7, lines 3, 38-39 and 6 -65;column 8, lines 15-16, "acetylsalicyclic" should read--acetylsalicylic-. Column 8, line 67, "560" should read --.560--; line69, "gar" should read --guar--. Column 9, line 11, "encapsulated, shouldread --encapsulated--.

Signed.and sealed this 8th day of June 1971.

(SEAL) Attaat:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR. Attesting OfficerCommissioner of Patents

